eMedicine Specialties > Hematology > Red Blood Cells and Disorders

Macrocytosis: Differential Diagnoses & Workup

Author: Wendy Brick, MD, Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Coauthor(s): Russell Burgess, MD, Department of Internal Medicine, Division of Hematology/Oncology, East Carolina Internal Medicine
Contributor Information and Disclosures

Updated: Aug 29, 2009

Differential Diagnoses

Alcoholism
Hemolytic Anemia
Hypothyroidism
Myelodysplastic Syndrome

Other Problems to Be Considered

Liver disease

Workup

Laboratory Studies

  • Complete CBC with platelet count
    • The hemoglobin/hematocrit level may provide a guide to diagnosis, and it determines presence and severity of anemia.
    • WBC and platelet count may be decreased in primary marrow disturbances.
    • The MCV is a calculated average volume of the erythrocytes. An MCV greater than 100 fL is, by definition, macrocytosis. Because evaluation of the RBC size is key to the diagnosis of an anemia, the MCV is considered to be the most important of the RBC indices.
  • Peripheral blood smear morphology may be helpful. Round macrocytes suggest liver or marrow infiltrative disease, whereas oval macrocytes tend to suggest a megaloblastic disorder.
    • This study provides clues to the etiology of macrocytosis.
    • Hypersegmented neutrophils and macro-ovalocytes strongly suggest megaloblastic anemia.
    • Nucleated RBCs, teardrop cells, decreased and/or large platelets, and immature WBCs are often present in myelophthisic disease and leukemias.
  • Reticulocyte count
    • This study helps to determine if hemolysis is present; it also indicates malfunctioning bone marrow.
    • Expect marked reticulocytosis (>4) in hemolytic anemias.
    • Reticulocyte count less than 1% indicates inadequate marrow production.
    • Reticulocyte count must be corrected for degree of anemia.
  • Coombs test
    • Perform this test if the reticulocyte count is elevated to aid in confirming the diagnosis of hemolysis.
    • Expect a positive direct Coombs test finding in autoimmune hemolytic anemias, hemolytic transfusion reactions, and some drug-induced anemias (eg, penicillin, methyldopa, some cephalosporins, sulfonamides).
  • Lactate dehydrogenase (LDH) is elevated in both intravascular and extravascular hemolysis including the ineffective erythropoiesis that occurs in megaloblastic anemias.
  • Because the haptoglobin binds free hemoglobin, a low or absent haptoglobin level indicates intravascular hemolysis.
  • If macro-ovalocytes and hypersegmented neutrophils are noted on peripheral smear, the vitamin B-12 level may be low.
  • RBC folate levels
    • If folate deficiency is the cause of the macrocytosis, the RBC folate level likely will be decreased.
    • As in vitamin B-12 deficiency, peripheral smear may reveal hypersegmented neutrophils and macro-ovalocytes.
  • Homocysteine level: Serum total homocysteine levels almost always are elevated in patients with folate deficiency, because folate is required in the remethylation step converting homocysteine to methionine. Serum methylmalonic acid and homocysteine levels may be increased even in early vitamin B-12 deficiency.
  • Serum unconjugated bilirubin is expected to be elevated in hemolysis.
  • If vitamin B-12 deficiency is the cause of the macrocytosis, the serum vitamin B-12 level likely will be decreased. Serum methylmalonic acid and homocysteine levels are increased early in vitamin B-12 deficiency, even before hematologic manifestations or decreases in B-12 levels are noted.
  • A Schilling test was previously considered the criterion standard to further investigate a low vitamin B-12 level. However, many institutions no longer offer the Schilling test. Alternative tests to the Schilling test are antibodies to parietal cells and intrinsic factor antibodies.
  • A serum folate level may be obtained, although an RBC folate level is more reliable because it reflects the level over the lifespan of the RBC.

Procedures

  • Bone marrow biopsy and aspirate
    • The bone marrow biopsy and aspirate determines if the marrow is functioning adequately and also may reveal replacement of marrow with tumor, granuloma, or fibrosis. Obtain the bone marrow prior to vitamin B-12 folate therapy or blood transfusion because megaloblastic changes may reverse rapidly.
    • The bone marrow in megaloblastic anemias is usually hypercellular with all cell lines proliferating. Marked erythroid hyperplasia may occur to the point at which the myeloid-erythroid ratio is reversed. Nuclear-chromatin dissociation with a young-appearing nucleus with abundant mature-appearing cytoplasm may occur. Granulocytic hyperplasia with giant metamyelocytes and bands often are noted.

Histologic Findings

  • Blood: On peripheral smear, large RBCs are evident. Depending on the etiology of the macrocytosis, peripheral smear may reveal nucleated RBCs, target cells, RBC fragments, hypersegmentation of neutrophils, immature WBCs, large platelets, or pancytopenia.
  • Marrow: Depending on the etiology of the macrocytosis, marrow may reveal hypercellularity, megaloblastic changes, fibrosis, infiltration by tumor or granulomatous disease, leukemic changes, or erythroid hyperplasia.

More on Macrocytosis

Overview: Macrocytosis
Differential Diagnoses & Workup: Macrocytosis
Treatment & Medication: Macrocytosis
Follow-up: Macrocytosis
References
Further Reading
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References

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Keywords

macrocytosis, macrocytes, megaloblasts, anemia, megaloblastic anemia, myelodysplastic anemia, myelophthisic anemia, aplastic anemia, acquired sideroblastic anemia, vitamin B-12 deficiency, folate deficiency, chronic alcoholism, alcoholism, accelerated erythropoiesis, chronic obstructive pulmonary disease, COPD, Lesch-Nyhan syndrome, deficient enzymes for folate metabolism, homocystinuria, liver disease, hypothyroidism

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Contributor Information and Disclosures

Author

Wendy Brick, MD, Consulting Staff, Department of Internal Medicine, Division of Hematology and Oncology, Mecklenburg Medical Group
Wendy Brick, MD is a member of the following medical societies: Alpha Omega Alpha, American College of Physicians, American Medical Association, and American Society of Hematology
Disclosure: Nothing to disclose.

Coauthor(s)

Russell Burgess, MD, Department of Internal Medicine, Division of Hematology/Oncology, East Carolina Internal Medicine
Russell Burgess, MD is a member of the following medical societies: American College of Physicians and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

Paul Schick, MD, Emeritus Professor, Department of Internal Medicine, Thomas Jefferson University Medical College; Research Professor, Department of Internal Medicine, Drexel University College of Medicine; Adjunct Professor of Medicine, Lankenau Hospital, Wynnewood, PA
Paul Schick, MD is a member of the following medical societies: American College of Physicians, American Heart Association, American Society of Hematology, International Society on Thrombosis and Haemostasis, and New York Academy of Sciences
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Ronald A Sacher, MB, BCh, MD, FRCPC, Professor, Internal Medicine and Pathology, Director, Hoxworth Blood Center, University of Cincinnati Academic Health Center
Ronald A Sacher, MB, BCh, MD, FRCPC is a member of the following medical societies: American Society of Hematology
Disclosure: Glaxo Smith Kline Honoraria Speaking and teaching; Talecris Honoraria Board membership

CME Editor

Rajalaxmi McKenna, MD, FACP, Consulting Staff, Department of Medicine, Southwest Medical Consultants, SC, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Emmanuel C Besa, MD, Professor, Department of Medicine, Division of Hematologic Malignancies, Kimmel Cancer Center, Thomas Jefferson University
Emmanuel C Besa, MD is a member of the following medical societies: American Association for Cancer Education, American College of Clinical Pharmacology, American Federation for Medical Research, American Society of Hematology, and New York Academy of Sciences
Disclosure: Nothing to disclose.

 
 
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